The enterovirus 71 (EV71) belongs to enterovirus genus of small ribosomal virus family. Since the first isolation of the virus in California in 1969, from North America, Europe, Australia to Asia, many outbreaks of EV71 are reported in succession worldwide. Over the past 20 years, the Asian-Pacific region suffers from EV71 seriously, which becomes the focus of health problems in some countries in the region. Infection of EV71 often causes slight symptom hand-foot-and-mouth disease (HFMD) in infants, however, it can be complicated with serious nervous system disease in some of the virus infected infants, such as aseptic meningitis, encephalitis and acute flaccid paralysis, or even death. For example, outbreak in Taiwan in 1998 causes 405 children cases in all have neurological complications, pneumonedema, pneumorrhagia and myocarditis, wherein 78 cases died. In 2008, HFMD cases are up to more than 6,000 cases in Fuyang city of Anhui province, wherein 24 children cases died, on May 2 in the same year, HFMD is included in category C statutory infectious diseases by the Ministry of Health to report and manage.
Over the past few decades, in order to eradicate poliomyelitis, the outbreak of epidemic diseases has been reduced greatly with progress obtained in efficient vaccine and public health undertakings. However, the emergence of EV71 poses a new threat to children, especially specific therapeutic drug and vaccine against such disease are absent currently. As to the serious cases resulted from EV71 infection, supporting treatment is still the main treatment method. Accordingly, it is an very urgent task to develop special antiviral drug against EV71 to protect children from harm resulted from EV71 virus infection.
EV71 belongs to picornaviridae, it is sense single strand RNA molecule containing about 7,400 nucleotides without capsule structure. In the early stage of infection, the viral particle binds to the receptors in host cells, and releases viral RNA into cytoplasm. Once the genome comes into the host cell, it uses viral RNA as the messenger RNA, which has its own internal ribosome entry site (IRES) and poly A tail, and is translated by cap independent mechanism, and encodes a polyprotein chain. After that, the polyprotein is cut into the mature viral functional protein under mediating by viral 2A protease and 3C protease. The viral RNA is not only the messenger RNA for translating protein, but also template required by the virus encoded RNA dependent RNA polymerase (RdRP, known as 3D) in the replication process. In the infected cell, the replication of viral RNA occurs in the tonoplast structure in cytoplasm. Different from 3D protein, 2C protein of virus is highly conservative among human enteric virus, and is deemed as a part of virus replication complex in tonoplast. After that, the offspring sense strand viral RNA is encapsulated by viral coat protein and is assembled into new infective virus particle. Finally, infection triggers apoptosis pathway by 2A protease and 3C protease, the host cell is lysed, and the new virus particles are released.
Maturation cleavage is key step in synthesis of EV71 protein. As to other human enteric viruses, 2A protease and 3C protease are important proteases in processing precursor polyprotein in virus.
The purpose of the present invention is to synthetize a new 3C protease inhibitor, for use in the preparation of a drug for preventing and/or treating viral diseases caused by small RNA viruses.